A drug prototype known as NZ-97 showed promise for treating pulmonary disease by stimulating growth of new stem cells to repair damaged tissue, based on data from a new proof-of-concept study.
In many pulmonary diseases, insufficient stem cells allow damage to progress, but researchers have developed a lung-targeted, drug-like small molecule to stimulate the growth of lung stem cells, according to data published in the Proceedings of the National Academy of Sciences.
Michael J. Bollong, PhD, an associate professor in the Department of Chemistry at Scripps Research, San Diego, California, and colleagues used ReFRAME, a drug repurposing library and database created by the Calibr-Skaggs Institute for Innovative Medicines (the drug discovery arm of Scripps Research) to test existing drugs as foundations to promote stem cell growth and repair in the lungs.
"At present, there are no drugs which promote regenerative repair of the lung," Bollong said in an interview. "This is especially important in idiopathic pulmonary fibrosis, as this disease is driven by an insufficiency of the stem cell population of the lower airway, alveolar type 2 cells (AEC2s), to proliferate and to regenerate the gas exchange epithelium," he said.
The researchers identified dipeptidyl peptidase 4 (DPP4) inhibitors as potential tools to help promote production of stem cells in the lower airway called AEC2s. Dysfunction of AEC2 is thought to play a key role in the pathogenesis of idiopathic pulmonary fibrosis, the researchers noted in the study. They created a new and highly soluble DPP4 inhibitor known as NZ-97 that could be administered via intratracheal injection.
In a mouse model of lung disease, NZ-97 induced the growth of AEC2 cells and improved damaged lung tissue. "Importantly, NZ-97 demonstrated good tolerability when dosed intratracheally every day in naive animals," the researchers wrote in the study.
In addition, 1 month of treatment with 0.5 mg/kg of NZ-97 every fourth day showed no detectable changes in alveolar structure, increased inflammation, or cellular hyperplasia.
The current research "identifies a novel mechanism for promoting alveolar repair" and treating not only idiopathic pulmonary fibrosis (IPF) but potentially other pulmonary diseases, such as chronic obstructive pulmonary disease, Bollong said.
"Here we reported a drug prototype, NZ-97, a locally delivered and lung-retained molecule that inhibits DPP4 in the lumen of the lung," Bollong explained. The NZ-97 prototype drug is chemically similar to CMR316, a new clinical drug candidate from researchers at Calibr-Skaggs that is scheduled to start a phase 1 clinical trial later in the summer of 2024, according to Bollong.
CMR316 is designed to be delivered once a week in mist form via a nebulizer. "If CMR316 demonstrates ameliorative efficacy in IPF, it could provide a novel avenue for regenerating the lung and could be added on top of standard-of-care anti-fibrotic drugs to delay or potentially even reverse disease progression," Bollong told Medscape Medical News.
"The key challenge will be understanding if the identified regenerative mechanism will show ameliorative efficacy in a clinical trial," Bollong said. "While we have shown effects in animal models and patient-derived cells, the degree and duration of the ameliorative effect in patients will ultimately be determined in the clinic."
Looking ahead, the CMR316 phase 1 clinical trial is designed to evaluate safety and target engagement, Bollong told Medscape Medical News. Bollong's lab also continues to collaborate with Calibr to develop other regenerative approaches to the treatment of disease in other organs, he said.
Meeting the Need for Regenerative Treatment
The current study and the ongoing research into NZ-97 address the need for regenerative therapies in pulmonary disease, said Dharani K. Narendra, MD, of Baylor College of Medicine, Houston, Texas, in an interview.
"Identifying DPP4 inhibitors, particularly NZ-97, as potential agents for expanding type 2 alveolar epithelial cells (AEC2s) represents a promising therapeutic strategy to stimulate the regeneration of damaged alveolar epithelium," she said. "The AEC2s play a crucial role in lung repair, and targeting these could potentially ameliorate various lung diseases that currently lack effective treatments," she explained.
"DPP4 inhibitors are well-established in diabetes management and have known biological actions; however, the successful repurposing and effectiveness of NZ-97 in promoting lung repair are surprising to some extent," said Narendra. "This surprise stems from this medication's novel application and efficacy in a pulmonary context, showing significant potential where traditional DPP4 inhibitors required higher, potentially unsafe doses to achieve similar effects," she said.
Should research prove successful, NZ-97 could offer substantial clinical benefits for treating pulmonary diseases such as IPF and other conditions involving alveolar damage. By enhancing AEC2 proliferation, NZ-97 may improve patient outcomes by mitigating lung damage and promoting regenerative repair, possibly reducing the dependency on more invasive treatments like lung transplantation.
More research on NZ-97 is needed in order to identify potential barriers to its use, Narendra told Medscape Medical News.
"Further studies are needed to evaluate the long-term effects of NZ-97, understand its mechanisms in human lung tissue, and determine its safety and efficacy in clinical settings," Narendra said.
Narendra had no financial conflicts to disclose but served on the Editorial Board of Chest Physician.